title: A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.
abstract: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Lymphoma Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mjrobert@iupui.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Justin
authors.initials: J
authors.lastname: Kline
authors.forename: Herbert
authors.initials: H
authors.lastname: Struemper
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: John W
authors.initials: JW
authors.lastname: Bauman
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Gardner
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Murray
authors.forename: Fiona
authors.initials: F
authors.lastname: Germaschewski
authors.forename: Jill
authors.initials: J
authors.lastname: Weisenbach
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Jonak
authors.forename: John F
authors.initials: JF
authors.lastname: Toso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D020382:Interleukin-18; D000069283:Rituximab